The Mannoprotein Cig1 Supports Iron Acquisition From Heme and Virulence in the Pathogenic Fungus Cryptococcus neoformans
The Mannoprotein Cig1 Supports Iron Acquisition From Heme and Virulence in the Pathogenic Fungus Cryptococcus neoformans
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DOI：
10.1093/infdis/jit029
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发表时间：
2013-04-15
影响因子：
6.4
通讯作者：
Kronstad, James W.
中科院分区：
文献类型：
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作者：
Cadieux, Brigitte;Lian, Tianshun;Kronstad, James W.
铁的获取对人类致病真菌新生隐球菌的毒力至关重要。细胞外甘露糖蛋白Cig1的隐球菌转录本受铁的高度调控，在缺铁的细胞中含量丰富，这表明它在铁的获取中发挥了作用。事实上，Cig1的缺失导致了在生理pH下血红素的生长延迟。CIG1的表达受pH反应转录因子Rim101的调控，Rim101的缺失也会损害血红素的生长。与野生型菌株相比，cig1增量突变体对非铁金属卟啉的敏感性较低，进一步表明Cig1在血红素吸收中发挥了作用。重组Cig1在血红素滴定中表现出血红素结合蛋白的吸收光谱，因此Cig1可能在细胞表面起到血球的作用。Cig1对隐球菌病小鼠模型的毒力有贡献，但只在缺乏高亲和力铁摄取系统的突变体中起作用。总体而言，Cig1介导的血红素摄取是新生葡萄球菌潜在的治疗靶点。
Iron acquisition is critical for virulence of the human pathogenic fungus Cryptococcus neoformans. The cryptococcal transcript for the extracellular mannoprotein Cig1 is highly regulated by iron and abundant in iron-starved cells, suggesting a role in iron acquisition. Indeed, loss of Cig1 resulted in delayed growth on heme at physiological pH. Expression of CIG1 is regulated by the pH-responsive transcription factor Rim101, and loss of Rim101 also impaired growth on heme. A cig1 delta mutant was less susceptible than the wild-type strain to noniron metalloporphyrins, further indicating a role for Cig1 in heme uptake. Recombinant Cig1 exhibited the absorbance spectrum of a heme-binding protein upon heme titration, and Cig1 may therefore function as a hemophore at the cell surface. Cig1 contributed to virulence in a mouse model of cryptococcosis but only in a mutant that also lacked the high-affinity iron uptake system. Overall, Cig1-mediated heme uptake is a potential therapeutic target in C. neoformans.